Current Oncology Reports (2018) 20:28

[Link]

MELANOMA (RJ SULLIVAN, SECTION EDITOR)

Mucosal Melanoma: a Literature Review

Simon Skovsted Yde 1 & Pia Sjoegren 1 & Martin Heje 1 & Lars B. Stolle 1

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Purpose of review Mucosal melanoma is of great interest due to its aggressive behavior and less favorable prognosis. The
literature is mainly case reports and case series. Here, we will collect the knowledge on mucosal melanoma from the last decade
and review the literature. The main focus is being site-specific clinical features, treatment, and prognosis.
Recent findings The use of immunotherapy gain ground as for others subsets of melanoma. Anti-CTLA-4 and anti-PD-1/ PD-L1
blockade in mucosal melanoma have been evaluated in recent studies. Clinical trials are ongoing.
Summary The etiology of mucosal melanomas remains unknown. Head and neck mucosal melanomas are most common. Wide
excision surgery is the treatment of choice. The effect of adjuvant therapy on survival remains questionable due to the limited
knowledge. Radiotherapy seems to give better local control. The overall five-year survival rate for mucosal melanomas is 0–45%.
Recent data indicates that this may be improved by the immunotherapy in the years to come.

Keywords Mucosal melanoma . Treatment . Surgery . Immunotherapy . Checkpoint inhibitors . CTLA-4 . PD-1 . PD-L1 . Ipilimumab .
Nivolumab . Pembrolizumab

Introduction Despite its rarity, mucosal melanomas are of great interest

due to their aggressive behavior and less favorable prognosis
Melanomas are malignant tumors arising from pigment compared to cutaneous melanomas. This could be because of
cells—melanocytes. Melanocytes are derived from the neural late diagnosis, patients’ delay and/or the obscured anatomic
crest cells and migrate to several sites [1]. They can arise from site of origin [4]. It may also be related to the rich lymphatic
both cutaneous and mucosal surfaces. Primary mucosal mel- and vascular supply of the mucosa.
anomas can be found in the mucosal membranes lining the The literature concerning this disease is primarily case re-
respiratory, gastrointestinal, and genitourinary tract [2]. The ports and case series. The aim of this paper is to summarize the
majority of melanomas are of cutaneous origin. Only 0.8– site-specific knowledge of mucosal melanomas by reviewing
3.7% are mucosal melanomas [3–5]. Due to the low inci- the published literature, with the main focus being clinical
dence, metastases from ocular and/or cutaneous melanoma features, treatment, and prognosis.
must be excluded to diagnose primary mucosal melanoma.
The condition was first described in 1856 by Weber et al. A
decade later, in 1869, mucosal melanoma was classified as its
own distinct disease by Lucke et al. [3]. Contrary to the rising Materials and Methods
incidence of cutaneous melanomas, the incidence of mucosal
melanomas is believed to remain stable [2]. A literature search was performed in PubMed using a series of
search strings as follows: “mucosal melanoma” OR “malig-
This article is part of the Topical Collection on Melanoma
nant melanoma” AND “oral”; “mucosal melanoma” OR “ma-
lignant melanoma” AND “sinonasal”; “mucosal melanoma”
* Simon Skovsted Yde OR “malignant melanoma” AND “respiratory”; “mucosal
Simonyde@[Link] melanoma” OR “malignant melanoma” AND “gastrointesti-
nal”; “mucosal melanoma” OR “malignant melanoma” AND
1
Plastic Surgical Research Unit, Department of Plastic Surgery,
“genital”; “mucosal melanoma” OR “malignant melanoma”
Aarhus University Hospital, Noerrebrogade 44, 8000 Aarhus AND “penile”; “mucosal melanoma” OR “malignant melano-
C, Denmark ma” AND “vagina”; “mucosal melanoma” OR “malignant
28 Page 2 of 9 Curr Oncol Rep (2018) 20:28

melanoma” AND “vulva”; “mucosal melanoma” AND “sys- Sheng et al. found that GNAQ/11 mutations occurred in
temic therapy”; “mucosal melanoma” AND “ipilimumab”; 9.5% of the patients. Two hundred eighty-four patients
and “mucosal melanoma” AND “nivolumab”. with mucosal melanoma from several primary sites of
origin were included. Significant shorter mean survival
Inclusion and Exclusion Criteria was found among the patients with GNAQ/11 compared
to patients with wildtype GNAQ/11 [9].
The search was limited to English language articles Furthermore, recent data suggests an increased frequency
concerning human studies exclusively, and with publication of c-KIT (CD117) in mucosal melanoma. C-KIT is
dates going back 10 years from February 2017. Primarily, case overexpressed in over 80% of cases. B-type Raf (BRAF) mu-
reports and review studies were included in the site-specific tations are uncommon in mucosal melanoma. Mutations in
search. All types of studies were included in the searches this gene are detected in less than 10% of cases. A reverse
concerning systemic therapy. pattern is observed in cutaneous melanomas [1, 7, 8, 10].
Articles concerning ocular malignant melanoma and cuta- Programmed death-ligand 1 (PD-L1) expression seems less
neous melanomas on the genitals were excluded. frequent in patients with mucosal melanoma. The reasons for
Titles and abstracts were screened to meet inclusion/ this finding remain unclear, but one hypothesis is that mucosal
exclusion criteria. The remaining papers were read by full text melanomas may be less immunogenic due to a lower muta-
and those not found to meet the inclusion/exclusion criteria tional burden [11•].
were excluded. Tumor staging for mucosal melanoma remains challeng-
ing. Several staging systems have been suggested, including
Literature tumor-nodal-metastases (TNM) staging systems, but none are
frequently used. TNM staging is only used for head and neck
The literature search revealed 293 articles in PubMed. Sixty- mucosal melanoma [1, 2].
seven case reports/series, 15 review articles, and five other A staging system should be valid as a prognostic tool to
types of articles were found to meet the inclusion/exclusion target treatment in terms of overall survival. This tool is not
criteria. yet identified. At this point, tumor thickness greater than
5 mm, more than 10 mitotic figures per high power fields
and/or ulceration has been suggested as independent prognos-
Epidemiology tic factors [1]. To develop a uniform staging system a more
thorough understanding of the prognostic factors is needed
Overall, the median age at diagnosis is 70 years for mucosal [6].
melanoma, which is decades later than for cutaneous melano-
mas [3, 4, 6]. For mucosal melanomas, no certain racial dif-
ferences are observed. This compared to cutaneous melano- Oral
mas, which are more common in Caucasians [3, 6, 7].
In addition, mucosal melanomas seems to be almost twice The search revealed 17 papers including 19 cases with oral
as frequent in females overall [3, 4, 6]. No association to mucosal melanoma [12–28]. The cases included 10 males and
human papilloma viruses, human herpes viruses, and 9 females aging from 32 to 87 years. The most frequent age of
pylomavirus has been drawn. The role of smoking has not diagnosis was from 50 to 80 years. Sixteen out of the 19 cases
yet been fully clarified [3, 6]. Due to their anatomic site of were of Asian background and only three were Caucasian.
origin, ultra violet (UV) light exposure is not considered a risk The general literature states that Japanese and Indians are
factor for mucosal melanoma [8]. The etiology of mucosal more often affected [1, 6, 27, 29].
melanoma remains unclear [2]. Pain and swelling occurred, but most of the cases were
asymptomatic. The primary site of origin was the palate
(6/19), maxilla (4/19), mandible (3/19), lip (3/19), buccal
Pathology and Staging (2/19), and parotid gland (1/19).
The lesions were macular or nodular with brown to black
The pathogenesis of mucosal melanoma is unknown. colors. Most tumors (11/19) were between 2 and 6 cm at the
However, changes in certain genes and metabolic path- time of diagnosis.
ways are known. Some reports indicate that mucosal mel- Approximately one third (6/19) presented with lymph node
anoma have several genetic changes in intracellular sig- metastases diagnosed by either elective modified lymph node
naling cascades. This may constitute the pathogenetic dissection of the neck (2/6), computerized tomographic (CT)
mechanism of melanoma. The ideal pathway to be scan (2/6), or clinical examination (2/6). Two of the patients
targeted remains unidentified [1]. In a recent report, with lymph node metastases had distant metastases at the time
Curr Oncol Rep (2018) 20:28 Page 3 of 9 28

of diagnosis. Only one patient had distant metastases without Sinonasal

lymph node metastases. Distant metastases were found in the
lungs, liver, bone, and brain. The search revealed nine papers including 13 cases with
Treatment was as follows: 13 patients received primarily sinonasal mucosal melanoma [32–40]. The cases included
surgery. Wide excision (9/13) was the most frequent excision four males and nine females aging from 53 to 85 years.
margin followed by narrow excision (4/13). Three patients Previous retrospective studies have reported both female and
received adjuvant radiotherapy. The dose was only reported male predominance. Diagnosis at earlier ages has also been
in one case (25 Gy/25 fractions). One patient received adju- reported [41, 42]. Only three out the 13 cases were of Asian
vant chemotherapy (not specified). One patient received only background. Most cases were Caucasian [42].
chemotherapy (fluroracil and cisplatin) as treatment [30]. Main symptoms were epistaxis and/or nasal obstruction
Another patient received radio- and chemotherapy as pallia- (10/13). The primary site of origin was maxillary sinus
tive treatment (not specified). Two patients died before treat- (5/13), nasal sinus (3/13), sphenoid sinus (2/13), nasopharynx
ment. One patient denied treatment and treatment was not (2/13), and not specified sinonasal (1/13). Historically, most
reported for one patient. sinonasal mucosal melanomas have been found within the
Four out of the 14 patients who received intentional cura- nasal cavity and less common in the paranasal sinuses [6,
tive treatment experienced recurrence. One had distant metas- 29, 41]. Most are polypoid and can assume dark, brown,
tases in the liver and was treated with chemotherapy (dimethyl red, or pale white colors. In seven out of 13 cases, tumors
triazeno imidazole carboxamide (DTIC), nimustine hydro- were larger than 2 cm at diagnosis. Tumor sizes in the remain-
chloride (ACNU), and vincristine) [17]. One had lymph node ing cases were not reported. None of the patients had lymph
metastases and was treated with radical neck dissection and node- or distant metastases at diagnosis.
adjuvant radiotherapy (not specified). Another had local re- Nine out of the 13 patients were primarily treated with
currence and was treated with wide margin re-excision (de- excision. Wide (3/9) and narrow (4/9) margins were equally
nied adjuvant radiotherapy). The last one had gastric metasta- frequent. Margins were not reported in two cases. One patient
ses and received palliative care. received unilateral neck dissection and two patients had adju-
Three out of 19 cases had no information about survival/ vant radiotherapy (not specified).
outcome. Of the remaining 16 cases, 11 were alive after 1 year Two patients were treated with only radiotherapy (35 Gy/5
(70%). fractions) and one patient had chemotherapy (cisplatin,
In the existing literature, surgical excision with tumor-free dacarbazine, and interleukin-2/interferon) combined with ra-
wide margins is the treatment of choice. In some cases, adju- diotherapy (carbon iron, 57.6 GyE/16 fractions) [35]. One
vant chemo- or radiotherapy is added. It has previously been patient refused treatment.
stated that patients with non-radical surgical excision have a Six out of the 13 cases developed distant metastases within
21-fold increased risk of dying of the disease in head and neck 1 year after the primary treatment. Of these cases, the initial
mucosal melanomas [1]. The statistical power can be treatment was narrow margin excisions (2/6), radiotherapy
questioned due to the low number of cases. If tumor-free ex- (2/6), wide margin excision (1/6), and no treatment (1/6).
cision is not obtainable, one should consider refraining from Distant metastases were found in the lungs, liver, bones and
surgery. It is previously stated that the likelihood of cervical heart. All cases received palliative radio- or chemotherapy
lymph node metastases increases when the tumor thickness is (not specified).
more than 5 mm [1]. Only four patients were alive after 1 year (31%). One out of
Based on a meta-analysis including 423 patients with 13 cases had no information on survival/outcome.
head and neck melanomas, Wushou et al. states that both In general, the incidence of nodal disease at the time of
surgery and nonsurgical procedures are negative prognos- presentation is low but not inconsiderable. The incidence
tic factors if done alone, and that surgery-based multiple ranges from 6 to 25% for nodal disease and approximately
therapy should be mandatory [27]. The same authors 10% for distant metastases [5, 29, 37]. The most frequent
found that primary postoperative adjuvant radiotherapy scenario is recurrence followed by distant metastases [8].
significantly improved loco-regional recurrence. No effect Over time, 40–50% will develop distant metastases in the
on overall survival was seen [31]. For patients with loco- lungs, brain, bones, and/or liver [2, 29].
regional recurrence without distant metastases, a second According to the literature, surgical excision, either
surgical procedure was considered the best option [1]. The open or endoscopically, is the treatment of choice. Due
effect of chemotherapy for oral mucosal melanoma is to the somewhat obscured locations, wide margins are
mainly casuistic and not fully investigated. challenging and in some cases impossible. Therefore, ad-
The prognosis of this disease is poor. In more recent pub- juvant radiotherapy is frequently used in these cases.
lications, the reported five-year survival is 15–45% [27, 30]. Neck dissection is reserved for patients with clinically
This coincides with the findings in the present cases. evident nodal involvement. Neck dissection does not
28 Page 4 of 9 Curr Oncol Rep (2018) 20:28

improve cumulative survival rates compared to local ex- Tumors of the mediastinum can originate from the thymus
cision alone [8]. and the trachea, among others. Due to the lack of literature,
Melanoma has traditionally been regarded as a radio resis- only little information is available. Only 10 cases have been
tant tumor. However, recent evidence suggests that radiother- presented over the years. Symptoms include chest pain and
apy alone or adjuvant treatment can be an effective modality bloody sputum. Primary treatment is radical surgery. At recur-
[43]. Follow-up of all patients is needed for further evaluation. rence, radio- and chemotherapy are used. The prognosis
Treatment with only chemo- or radiotherapy is rare, but can seems poor [46, 48].
in some cases be the only possibility. The use of systemic Mucosal melanoma of the lungs is also extremely rare.
therapy for sinonasal melanomas is controversial. No effect Less than 30 cases in the English language literature are re-
on overall survival is seen. It is widely used for palliative ported. They represent only 0.01% of all primary lung tumors
treatment [44]. [47]. Since most melanoma lesions of the lungs are metastatic,
The prognosis of sinonasal mucosal melanoma is poor. The extrapulmonary primary lesions must be ruled out initially [2].
five-year survival rate is 0 to 31%. The lowest survival rates Pulmonary mucosal melanoma is mostly seen in males in their
are seen for those with sinus melanomas [2, 43]. mid-fifties [47].
The symptoms are cough, haemopthysis, shortness of
breath, and dusty sputum [45, 47]. The primary treatment is
wide excision (wedge, lobectomy, or pneumonectomy) and
Respiratory Tract complete lymph node resection. The effect of radio- and che-
motherapy remains unknown [2].
We define the respiratory tract as including the larynx, the The present cases indicate very poor prognosis and great
mediastinum, the trachea, and the lungs. Mucosal melanomas metastatic potential. Prognostic factors remain unknown due
in these areas are extremely rare and scantily described in the to lack of large series [45, 47].
literature. Only six cases in five papers were identified
[45–49]. The cases included three males and three females
aging from 32 to 71 years. Five patients were of Asian back- Gastrointestinal Tract
ground. Symptoms were related to the primary site of origin
and will be described later. The primary sites of origin were Twenty-one papers revealed 21 cases of mucosal melanoma in
the lungs (3/6), trachea (1/6), thymus gland (1/6), and larynx the gastrointestinal tract [7, 10, 50–59]. The cases include 13
(1/6). Most tumors (4/6) were larger than six centimeters. males and 8 females aging from 36 to 87 years. Diagnosis is
When reported, no evident lymph node or distant metastases most often seen in the sixth and seventh decades of life.
were seen (5/6). Four out of the six patients were treated with Thirteen out of 21 cases were Caucasian.
excision (two with wide margins and two with unknown mar- The primary sites of origin were the esophagus (5/21),
gin). One had neoadjuvant therapy (4 cycles of BEP stomach (2/21), small intestine (6/21), colon (2/21), anorectal
(bleomycin, etoposide platinum) and 2 cycles of TIP (5/21), and liver (1/21). According to the existing literature,
(aclitaxel, ifosfamide, cisplatin)) [46]. One received adjuvant the anorectal was the most common site of origin, while the
chemotherapy (dacarbazine, not specified). One out of the six esophagus, small intestine, and colon were the less common
patients was treated with only chemotherapy (dacarbazine, not [2, 60].
specified). One refused treatment. Five cases of esophageal mucosal melanoma were identi-
Half of the patients had recurrence and/or distant metasta- fied. Up to 2011, 337 cases were reported. Of those, 277 were
ses within 1 year. Distant metastases were found in the lungs, among Japanese people [2, 61]. In concordance with the liter-
liver, and bones. Half of the patients died within 1 year (50%). ature, male predominance is seen (4/5) [62].
Due to the small number of cases, no trends can be identified. The primary lesions were located 25 to 41 cm from the
Mucosal melanoma of the larynx is extremely rare. Only 60 incisors. The most common symptoms were dysphagia and
cases are reported in the literature [2]. Laryngeal mucosal abdominal discomfort/pain. Melena and hematemesis were
melanoma is mostly seen in males in their sixth and seventh also reported, but less frequently [62]. The tumor was more
decade. The symptoms are dysphagia, hoarness, and painfull/ than two centimeters in three cases and not reported in the
sore throat [2, 29, 49]. remaining two. The tumors can be flat, polypoid, and protrud-
The primary treatment is complete surgical removal. ing with black colors. Four patients had no lymph node or
Radiotherapy can improve loco-reginal control, but have no distant metastases. Only one presented with lymph node and
effect on overall survival [31]. distant metastases. Distant metastases were seen in the lungs,
Despite treatment, the prognosis is poor. Local recurrence liver, brain, and bones. In addition, distant metastases in the
after treatment is around 20%. The five-year survival is less mediastinum were reported [62]. Three patients had surgery,
than 10% [2, 29]. two with wide margins. The patient who had lymph node and
Curr Oncol Rep (2018) 20:28 Page 5 of 9 28

distant metastases at diagnosis was treated with chemotherapy liver, and brain. They all died within the first year. For two
(masitinib 7,5 mg/kg/day, administrated twice daily) [63]. One patients, follow-up was inadequate. Only one patient was
patient did not receive treatment. alive after 1 year. The prognosis is considered extremely
The treatment of choice was wide surgical excision. In case poor.
of severe morbidity, treatment should be considered carefully. Two cases of mucosal melanoma in the colon were identi-
The follow-ups in the present cases were inadequate and no fied. Both were males and in their mid-60s. Only seven cases
tendency on outcome/survival could be identified. However, it including the present cases are reported. A slightly male pre-
should be noted that one patient lived more than 7 years after dominance is seen. The age of diagnosis was 41 to 84 years
total esophagectomy and lymph node dissection with no re- [51]. The symptoms in the present cases were melena, nausea,
currence. In total, seven patients lived more than 5 years after weight loss, and intermittent diarrhea. These are the same
receiving this treatment [62]. Therefore, it might be the treat- symptoms as for other colonic tumors. One had no lymph
ment of choice. More investigations are needed. node or distant metastases. The other had multiple enlarged
The overall prognosis is poor. The mean survival after sur- axillary lymph nodes and lungs metastases diagnosed with a
gery is 12–15 months [2, 62]. The 5 year survival is only 2, 3– CT scan. One had palliative care and died after 4 months. The
37% [2, 63]. other patient had wide excision. Outcome was not reported.
Two cases of mucosal melanoma in the stomach were iden- Little information on treatment and prognosis is available.
tified, one male and one female. Generally, there are only 20 Mucosal melanoma of the colon should probably be treated as
cases of primary gastric melanoma in the English language other colonic tumors. The prognosis remains unknown, but
literature, making it exceptionally rare [23]. No sex predilec- might be as poor as for the other gastrointestinal malignant
tion has been found. The 50-year-old female was treated with melanomas.
gastrectomy and lymph node dissection due to multiple posi- Five cases of anorectal mucosal melanoma were identified.
tive perigastric lymph nodes. Follow-up was only 4 months Four out of five were female. Age ranged from 39 to 83 years.
without recurrence [64]. The 71-year-old man was treated Diagnosis is most often seen in the fifth to the seventh decade
with temozomide due to multiple distant metastases. The pa- of life [7, 50]. Rectal bleeding is the most common symptom.
tient died after 2 cycles due to progressive disease [65]. No The lesions can be polypoid or nodular and brown/black in
conclusion can be drawn. color. Three patients had neither lymph node or distant metas-
Surgery should be considered in case of cure resectable tases at diagnosis. One had lymph node metastases diagnosed
disease. The role of adjuvant chemo- and radiotherapy re- after wide excision. Another had multiple metastases in the
mains unknown. lungs and liver diagnosed with a CT scan. In the present cases,
The prognosis is extremely poor. The literature states that three had no evidence of distant metastases at diagnosis. The
the median survival time from diagnosis is 5 months. The five- general literature states that 20 to 70% of the patients will have
year survival rate is only 3% [64]. metastases at the time of diagnosis [10, 50]. Anorectal malig-
Six cases of mucosal melanoma in the small intestine were nant melanoma metastasizes to the mesorectum, inguinal
identified. Only 40 cases including the present have been re- lymph nodes, liver, lungs, bones and brain [50].
ported [52]. Male predominance was seen (4/6). Age ranged Associations to human immunodeficiency virus (HIV) are
from 52 to 72 years. The disease is considered more aggres- suggested [7, 50].
sive in younger patients [52, 56]. The tumors were mainly Three were treated with wide margin excision (two with
polypoid, but can also be cavitary, infiltrating, or exoenteric adjuvant interferon [50, 55]), one with close margins and one
[52]. Half of the tumors were larger than 5 cm at diagnosis. had palliative radiotherapy (dose unknown). Besides the pal-
Four out of six patients had lymph node involvement at diag- liative patient, three patients had developed distant metastases
nosis. None had distant metastases. All the patients were treat- within 1 year. Overall, half of the patients died within 1 year.
ed with wide excision. Only one had groin dissection due to For the rest, follow-up was inadequate.
positive sentinel node biopsy. One patient had adjuvant ther- Extensive surgery including abdominoperineal resection
apy with interferon [57]. seems to be the treatment of choice. However, no difference
If the disease is not disseminated, extensive surgery in- in survival is observed compared to wide local resection [7,
cluding wide resection of the tumor with a wedge of the 60]. Adjuvant radiotherapy improves local control, but does
mesentery to remove the regional lymph nodes is the treat- not improve survival [2]. Adjuvant chemotherapy and inter-
ment of choice [52, 56]. Adjuvant chemotherapy has been feron is widely used, but the effect can be questioned. Due to
tried, but the effect has not been established. Dogán et al. the high number of metastases at diagnosis, the prognosis is
treated their patient with chemotherapy (temozolimide), poor. The five-year survival rate is 10–20% [7, 10].
when distant metastases were diagnosed. The effect was One case of mucosal melanoma in the liver was identified.
poor [57]. Half of the patients developed distant metastases The patient was treated with wide local excision and received
within 6 months. Distant metastases were seen in the lungs, adjuvant interferon. Initially, no signs of lymph node or distant
28 Page 6 of 9 Curr Oncol Rep (2018) 20:28

metastases were seen. Recurrence was found after 5 months. metastases are lungs, liver, and brain [2]. Surgery is the best
Outcome and further treatment was not reported [53]. available treatment. However, radical surgery does not im-
prove survival. Less invasive procedures should be considered
if clear margins can be obtained [60]. Adjuvant therapy with
Female Genitourinary Tract interferon is widely used. The effect is questionable. The prog-
nosis is extremely poor. The five-year survival rate is 0–21%
Thirteen cases from 9 papers with mucosal melanoma in the [2, 60, 70].
female genitourinary tract were identified [66–74]. Both mu- Four cases of vulvar mucosal melanoma with patients ag-
cosal and cutaneous surfaces are present on the vulva. ing from 14 to 71 years were identified [67, 69, 70, 74]. Three
Cutaneous cases are beyond the scope of this paper and will out of four were older than 50 years. Pain, itching, or bleeding
not be discussed. occurred, but the disease can be asymptomatic. In three cases,
Nine out of the 13 cases were Caucasian. Age at diagnosis the tumor was larger than 2 cm and pigmented. The tumors
ranged from 14 to 89 years. The primary site of origin was the were papilllomatous or flat. None of the patients had lymph
cervix (1/13), vagina (6/13), vulva (4/13), and urethra (2/13). node or distant metastases at diagnosis. Two patients had wide
Mucosal melanoma in the urinary bladder and the ovary are excision and lymph node dissection. Two patients had exci-
reported [2, 75]. sion with narrow margins. One had sentinel node biopsy.
One case of cervical mucosal melanoma was identified Outcome was not reported in two cases. One had no recur-
[71]. Little can be drawn from that case. Women older than rence after 1 year. The last patient had local recurrence after 4
50 years are most often affected [2]. Most common symptoms and 6 years. The recurrences were treated with external beam
are vaginal bleeding and vaginal discharge. Macroscopically, radiation therapy and permanent interstitial brachytherapy
the lesions can present as exophytic, polypoid, or plane [71]. [67]. None of the patients were reported to have died.
Despite radical surgery and adjuvant chemotherapy with In the literature, cutaneous, and mucosal vulvar melanoma
cisplantin-vindesine-dacarbazine, the patient experienced re- are traditionally considered as one group. Hence, little litera-
lapse after 18 months and died after 64 months. No report of ture on only mucosal vulvar melanoma is available. Optimal
nodal or distant metastases was available. This indicates high- treatment is unknown. As in other areas of the female genital
ly aggressive behavior. Radical surgery with invalidating con- tract, surgery might be the treatment of choice. Considerations
sequences for the patients should be considered carefully. The on treatment will be the same as for vaginal mucosal melano-
five-year survival rate has previously been reported as only ma. Prognosis is unknown, but might be poor.
10.7% [2]. Two cases of urethral mucosal melanoma were identified
Six cases of vaginal mucosal melanoma aging from 31 to [66, 73]. Both patients were in their sixties. Their symptoms
89 years were identified [68, 70, 72]. The most common were palpable mass and voiding difficulties, respectively. The
symptom was vaginal bleeding (5/6). The tumor was larger most common symptoms are urethral mass, dysuria, urethral
than two centimeters in five cases. Ulceration was seen in discharge, hematuria, or urethral pain [8, 73]. The tumors were
three cases. Macroscopically, the tumors can present as nodu- one and 2 cm in size. The lesions can be polypoid masses and
lar or papilllomatous pigmented masses. One out of the six pigmented or amelanotic [2]. There were no lymph node or
cases was amelanotic. The tumors are most often located in distant metastases. Both patients had wide excision, for one of
the lower third and anterior wall of the vagina [2]. Only one them including lymph node dissection The patient who had
patient had lymph node metastases, diagnosed after lymph received the more severe treatment died after 14 months with
node dissection. None had distant metastases. All patients multiple metastases. The other was alive after 1 year.
had wide excision surgery. In three cases, lymph node dissec- Surgery with tumor-free margins seems to be the treatment
tion was done. Four patients had adjuvant interferon [70] and of choice to achieve local control. Inguinal lymph node dis-
one had adjuvant chemotherapy (dacarbazine) [68]. One pa- section has no effect on survival [73]. Thus, optimal extent of
tient was lost to follow-up. Three patients died from wide- surgery remains unclear [2]. Divagating information on the
spread disease within 2 years. Two patients were alive after effect of chemotherapy is reported [66, 73]. Further evalua-
2 years. One of them had experienced local recurrence three tions are needed. The disease can be extremely aggressive
times and brain metastases and had been treated with excision [66]. The three-year survival rate is only 27% [2, 73].
(margins unknown). Previously, it has been hypothesized that
tumor sizes smaller than two to three centimeters makes for
better chances of survival [2, 70]. Despite no nodal or distant
metastasis, the prognosis is poor. Lymph node metastasis is Male Genitourinary Tract
considered a negative prognostic factor [2]. Sentinel node bi-
opsy should be considered, to target the treatment, based on As for the female genitourinary tract, only cases concerning
expected survival [7, 60]. The most common sites of distant mucosal melanomas are included in this article.
Curr Oncol Rep (2018) 20:28 Page 7 of 9 28

Five cases were identified in five papers [76–80]. Age at each been examined in small studies and formed the basis of
diagnosis ranged from 53 to 72 years. Three patients were ongoing clinical trials examining novel approaches.
Caucasian and two were of Asian background. In three cases, The systemic treatments for distant disease often follow
primary site of origin was the glans penis. In two cases, the established paradigms for cutaneous melanoma.
penis shaft and urethral meatus was involved, respectively. In recent years, immunotherapy has become increasingly
Primary site on the inner blade of the prepuce are reported. dominant in the treatment of metastatic melanoma.
The glans penis is considered the more frequent site of origin Ipilimumab (a cytotoxic T-lymphocyre antigen-4 checkpoint
[8, 81]. Penile mucosal melanoma was most often asymptom- inhibitor) was approved by the U.S. Food and Drug
atic. Non-healing lesions and urinating difficulties occurred. Association (FDA) in 2011 and has become a standard of care
The lesions were pigmented with brown to black colors. for patients with unrectable or metastatic melanoma.
Ulceration was seen in two cases. The lesions can also be Nivolumab and pembrolizumab (PD-1 checkpoint inhibitors)
polypoid and papilllomatous [77, 81]. Two patients had lymph were approved by the U.S. FDA in 2014.
node metastases. One of these had clinically palpable lymph- In 2013, Postow et al. presented a multicenter, retrospective
adenopathy. None had distant metastases at diagnosis. Distant analysis of 30 patients with mucosal melanoma treated with
metastases were reported in the lungs, liver, bones, testes, ipilimumab. The authors concluded that the overall response
bladder, and brain [82]. rate was low. The median overall survival rate from the first
All patients were treated with excision primarily. Wide ex- dose was 6.4 months. Additional investigation was found nec-
cision was the most frequent excision margin (3/5). In four essary to clarify the role of ipilimumab in patients with muco-
cases, lymph node dissection was included. Three patients sal melanoma [84]. Their findings were consistent with the
received adjuvant interferon [76, 78, 79]. One patient received findings of Simeone and colleagues [85]. In addition, they
adjuvant chemo- (bleomycin, vincristine, and cisplatin) and found that both disease control and survival were significantly
immunotherapy (thymycin) [80]. associated with decreasing levels of lactate dehydrogenase
For three patients, no recurrence was reported after (LDH).
10 months, 1 year, and 5 years, respectively. In 2016, Ascierto et al. reported a case of complete re-
The patient who was primarily treated with narrow margin sponse from nivolumab monotherapy. After 20 years of treat-
excision experienced local recurrence after 5 years. Treatment ment initiation, the patient was disease-free and treatment was
was total penectomy and bilateral inguinal lymph node dis- stopped.
section. Further outcome was not reported. Outcome was not The patient was a part of an industry funded clinical phase
reported in one case. III study comparing nivolumab and with dacarbazine. The
Previous papers report five-year survival rates from 10 to primary endpoint was overall survival. Patients with metasta-
20% [8, 82]. tic melanoma from both cutaneous and mucosal primary sites
were included. The authors suggested the need to identify
patients who wound achieve the greatest benefit from
nivolumab monotherapy [86•].
Systemic Therapy A multicenter, retrospective cohort analysis, published in
2016, by Shoushtari et al. addressed the exact need for that.
Systemic therapy for melanoma has been of great interest for The aim of the study was to evaluate the efficacy of
the last decade. Initially, most studies initially evaluated sys- pembrolizumab and nivolumab for patients with metastatic
temic therapy used for metastatic melanoma from primary mucosal melanoma. Thirty-five patients were included. The
cutaneous sites [83]. Over time, more studies involving sys- response rate was 23% after median follow-up of 10.6 months.
temic therapy for mucosal melanoma have been published. The median progression-free survival was 3.9 months. The
In 2015, Spencer et al. published a very extensive and authors found the response rates comparable to the published
thorough review article including systemic therapy for muco- rates in patients with cutaneous melanoma and support the
sal melanoma [3]. The authors found no consensus guidelines routine use of pembrolizumab and nivolumab in clinical prac-
on the optimal systemic therapy. Most conclusions are based tice [87•].
on case reports with a limited number of patients. At that time Most recent study, by D’Angelo et al., evaluated the effi-
of publishing, no systemic therapy showed significant im- cacy of ipilimumab and nivolumab alone and in combination.
proved outcomes. The median overall survival rate reported The study included a pooled analysis of data from clinical
with most treatment regimens were 4.9–9.7 months. studies. In total, 889 melanoma patients were included.
In the article, systemic therapy options included chemo- Approximately 10% had mucosal melanoma. The authors
therapy (cisplatin, vinblastine, dacarbazine, interferon), found that ipilimumab and nivolumab in combination seems
targeted therapies (imatinib, temozolomide), and immunother- to have greater efficacy than either agent alone. Ipilimumab
apies (ipilimumab, pembrolizumab/nivolumab). They had was found to be the less favorable as monotherapy. When
28 Page 8 of 9 Curr Oncol Rep (2018) 20:28

combining nivolumab and ipilimumab, the response rate was 4. Postow MA, Hamid O, Carvajal RD. Mucosal melanoma : patho-
genesis, clinical behavior, and management. Curr Oncol Rep.
found to be 37.5%. The progression-free survival rate was
2012;14:441–8.
5.9 months. Adverse events were observed at 40.0% of the 5. Moreno MA, Hanna EY. Management of mucosal melanomas of
patients [11•]. the head and neck : did we make any progress? Curr Opin
Otolaryngol Head Neck Surg. 2010;18(2):101–6.
6. Patrick RJ, Fenske NA, Messina JL. Primary mucosal melanoma. J
Am Acad Dermathology. 2007;56:828–34.
7. Seetharamu N, Ott PA, Pavlick AC. Mucosal melanomas: a case-
Conclusion based review of the literature. Oncologist. 2010;15:772–81.
8. Tacastacas JD, Bray J, Cohen YK, Arbesman J, Kim J, Koon HB,
et al. Update on primary mucosal melanoma. J Am Dermatology.
Primary mucosal melanomas are rare but aggressive tumors.
2014;71:366–75.
The existing literature is limited. The etiology of mucosal 9. Sheng X, Kong Y, Li Y, Zhang Q, Si L, Cui C, et al. GNAQ and
melanomas remains unknown. Head and neck mucosal mela- GNA11 mutations occur in 9.5% of mucosal melanoma and are
nomas are most common. A universal TNM staging system is associated with poor prognosis. Eur J Cancer. 2016;65:156–63.
10. Itoh M, Goto A, Wakasugi H, Yoshida Y, Matsunaga Y, Fujii K, et al.
missing. At this point, TNM classification is only used for
Anorectal melanoma with a KIT-activating mutation, which is a target
head and neck mucosal melanomas. Wide excision surgery for tyrosine kinase inhibitor. Int J Clin Oncol. 2011;16:428–34.
is the treatment of choice. Due to the somewhat obscured 11.• Angelo SPD, Larkin J, Sosman JA, Lebb C, Brady B, Neyns B,
anatomic site of origin, excision margins remain individual, et al. Efficacy and safety of nivolumab alone or in combination with
having patient morbidity in mind. The effect of adjuvant ther- ipilimumab in patients with mucosal melanoma : a pooled analysis.
J Clin Oncol. 2017;35:226–35. For mucosal melanoms,
apy on survival remains questionable due to the limited nivolumab combined with ipilimumab seemed to have greater
knowledge. Radiotherapy seems to give better local control. efficacy than either agent alone. However, the incidence of
The overall five-year survival rate for mucosal melanomas is grades 3 or 4 treatment-related adverse events was 40.0% for
0–45%. Recent data indicates that this may be improved by combination therapy. Patient selection is of great importance.
12. Boulaadas M, Benazzou S, Mourtada F, Sefiani S, Nazih N,
the immunotherapy in the years to come. The prognosis seems Essakalli L, et al. Primary oral malignant melanoma. J og craniofa-
more favorable for head and neck mucosal melanomas. This cial Surg. 2007;18:1059–61.
could be due to the staging system and more standardized 13. Auluck A, Zhang L, Path DO, Frcd C. Primary malignant melano-
treatment. ma of maxillary gingiva —a case report and review of the literature.
Clin Pract. 2008;74:367–71.
Further investigations, including a universal staging system 14. Kumar SKS, Shuler CF, Sedghizadeh PP, Kalmar JR. Oral mucosal
and standardized treatment, will probably increase the melanoma with unusual clinicopathologic features. J Cutan Pathol.
outcome. 2008;35:392–7.
15. Tsutsumida A, Yamamoto Y, Sekido M, Itoh T. Suspected case of
primary malignant melanoma of the parotid gland. Scand J Plast
Compliance with Ethical Standards Reconstr Surg Hand Surg. 2008;42:105–7.
16. Godoy GP, de Castro Gomes DQ, Pereira JV, de Queiroz
Conflict of Interest Simon Skovsted Yde, Pia Sjoegren, Martin Heje, Figueiredo RL, Nonaka CFW, da Costa Miguel MC.
and Lars B. Stolle declare they have no conflict of interest. Desmoplastic melanoma of the lower lip: a case report. Oral Surg
Oral Med Oral Pathol Oral Radiol Endodontol. 2009;108:e64–9.
Human and Animal Rights and Informed Consent This article does not 17. Umeda M, Murata M, Suzuki H, Yanagida T, Shibuya Y, Komori T.
contain any studies with human or animal subjects performed by any of A case of malignant melanoma of the oral cavity alive with liver
the authors. metastasis for a long period with administration of a biologic re-
sponse modifier, OK432. Kobe J Med Sci. 2010;56:140–7.
18. Reddy B, Sridhar GR, Anuradha CH, Chandrasekhar P,
Lingamaneni KP. Malignant melanoma of the mandibular gingiva:
a rare occurrence. Indian J Dent Res. 2010;21:302–5.
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